NK cells are effector lymphocytes playing a critical role in the natural resistance against tumors. However, the precise mechanisms underlying NK cell-mediated natural resistance against tumor metastasis are still unrevealed. B16 cells, mouse melanoma cells, were resistant to freshly isolated NK cell-mediated killing; nevertheless, NK cells were critical for natural resistance against experimental lung metastasis of B16 cells. We found that lung metastasis was increased significantly in IFN-γ^–/– mice but not pfp^–/–, IFN-αR^–/–, or IL-12/IL-18^–/– mice. Interestingly, freshly isolated lung NK cells, but not spleen or liver NK cells, displayed augmented IFN-γ production after B16 inoculation. Adoptive transfer of pfp^–/– NK cells, but not IFN-γ^–/– NK cells, significantly decreased B16 lung metastasis in IFN-γ^–/– and pfp/IFN-γ^–/–mice. Lung metastases of IFN-γRDN B16 was also increased in NK cell-depleted or IFN-γ^–/– mice, suggesting that the IFN-γ response of host cells was required in the NK cell and IFN-γ-mediated antimetastatic effect. Our results demonstrate that IFN-γ production from lung resident NK cells is a key response in the natural resistance to the experimental lung metastasis of NK cell-resistant tumor cells.